Method of treating multiple sclerosis

ABSTRACT

The invention provides methods for treating multiple sclerosis by administering biotin. The invention also provides methods for treating sequalae after multiple sclerosis attacks by administering biotin.

The invention relates to the treatment of multiple sclerosis, and inparticular of the progressive forms and of the neurological sequalaeafter attacks of the disease.

Multiple sclerosis (MS) is a frequent and disabling neurological diseasecharacterized by multifocal destruction of central nervous systemmyelin.

The prevalence of MS in Europe is approximately 1/2000 inhabitants(Noseworthy et al., 2000). The disease typically begins between the agesof 20 and 30 and affects twice as many women as men. In 80% of cases,the disease initially evolves through attacks which result completely orwith sequalae in a few weeks or months (pure remitting phase or emittingphase with sequalae). However, in 40% to 70% of cases, patients whoexperience an initially remitting evolvement subsequently evolve towardsa progressive form (secondary progressive form). In 20% of patients, theevolvement is immediately progressive without attacks (primaryprogressive form).

For patients who experience an evolvement via regressive attacks, theremissions are less complete over time, resulting in functionalsequalae, the ability to walk being to on average 20 years after thebeginning of the disease.

Thus, the conventional form of multiple sclerosis can have threeevolutive modes:

Relaxing-remitting form: exacerbations alternating with remissionsduring which partial or total recovery is observed. The remissions canlast months or years. The exacerbations can occur spontaneously or betriggered by certain external factors, such as an infection, post-partumor certain vaccinations.

Primary progressive form: The disease evolves progressively withoutremissions, with the possibility of evolutive plateau during which thedisease does not progress. Contrary to the cyclic tendency, there are noclear exacerbations.

Secondary progressive form: This form follows on from a remitting formwhich begins with attacks alternating with remissions, followed by agradual progression of the disease without identifiable attacks.

Pyramidal syndrome marks the beginning of (reveals) the disease in 20%of cases, and manifests itself through walking problems with highfatigability, spasticity, exaggerated reflexes in the lower limbs, thepresence of a Babinski sign, no abdominal cutaneous reflexes. At the endof the attack, the Babinski sign often remains as a sequela.

Retrobulbar optic neuritis is also an indication of the disease in closeto a third of cases: it is the most evocative symptom. It manifestsitself for the patient through a rapid and profound decrease in visualacuity, ocular and orbital pain, increased with eye movements, centralor cecocentral scotoma and colour blindness (dyschromatopsa of thered-green axis). At the acute stage, the back of the eye is normal, andit is only after about 15 days that atrophy of the papilla occurs,testifying to the damage to the optic nerve and sometimes persistent asa sequela. The visual evoked potentials are impaired, with slowing ofthe P100 wave.

Sensory problems are common. They are essentially subjective:paresthesia, pins and needles, Lhermitte's sign (electric shocksensation running down the spine when flexing the neck). A posteriorcordonal syndrome with deep sensory disorders is sometimes found, andmore rarely involvement of the spinothalamic tract with thermalgesicanaesthesia. Facial pain (or, conversely, anaesthesia) is possible inthe event of the trigeminal nerve being affected in its bulbar portion.

The disease may also manifest itself through:

A vestibular syndrome combining rotary vertigo, nystagmus and ataxia;

A cerebellar syndrome. Demyelinated plaques are frequent in thecerebellum and in the posterior fossa, which can produce a cerebellarsyndrome with an unstable upright stance, walking as if inebriated,movements which are dysmetric, etc.;

Diplopia consisting of a sensation of double vision due to paralysis ofone or more oculomotor muscles. Internuclear ophthalmoplegia is possiblein the event of involvement of the posterior longitudinal bundles (whichlink the nuclei of the oculomotor nerves and ensure that they operateharmoniously), which manifests itself in the lateral gaze through anincomplete adduction of one eye associated with nystagmus of the eye inabduction;

Genito-sphincteric disorders are frequent and are linked to spinal cordinvolvement. They manifest themselves through urinary urgency (orurinary retention), constipation and impotence. These disorders are asource of acute urine retention, and urinary infections;

Facial paralysis;

Asthenia (fatigue), a frequent symptom of multiple sclerosis, issometimes the one which is the most debilitating.

Multiple sclerosis is generally considered to be an autoimmune diseasewhich occurs on a carticular genetic background (Weiner, 2004; Chaudhuriet al., 2004). From the neuropathological point of view, the disease ischaracterized by demyelinated plaques, well-defined hypocellularregions, within which are observed a scarcity of myelin, an astrocyticgliosis and sometimes an inflammatory infiltrate which, when it ispresent, attests to the active nature of the disease. With time (butsometimes early on), there are also irreversible axonal lesions, themechanism of which is poorly understood.

Thus, it is possible to distinguish two components in thephysiopathology of multiple sclerosis: (1) an inflammatory component,responsible for the evolutive attacks, and beginning with the arrival ofCD4+ T lymphocytes in the central nervous system (Weiner, 2004), and (2)a degenerative component, the mechanism of which is for the momentpoorly understood (Chaudhuri et. al., 2004).

Interferon beta and glatiramer acetate have proven to be effective inmultiple sclerosis (attacks less numerous and less severe, improvementof lesions visible by MRI, sometimes a less evolutive nature of thehandicap).

The indications for interferon treatment are remitting MS with at leasttwo attacks over the previous two or three years, or secondaryprogressive MS with persistence of attacks (continuous and progressiveworsening, without remission between the acute phases). The currenttendency is to begin the treatment early, as soon as the first attackoccurs under certain conditions since it could then reduce thefunctional sequalae. However, the long-term efficacy remains disputed(Filippini G, Munari L, Incorvaia B et al. interferons in relapsingremitting multiple sclerosis a systematic review [archive], Lancet,2003; 361: 545-552).

Glatiramer acetate, for its part, is a copolymer consisting of severalamino acids. It appears to space out the attacks in ambulatory patients(who can still walk on their own) suffering from multiple sclerosisevolving through attacks, of relapsing/remitting type, characterized byat least two attacks over the course of the previous two years, aseffectively as interferon. It appears to act by causing immune toleranceof the lymphocytes with respect to myelin constituents.

Natalizumab (Tysabri) is a monoclonal antibody directed against theleukocytes integrin alpha-chain. It can be proposed in remitting MS,either as frontline treatment in severe cases (two attacks in one yearwith sequalae) or after failure of interferons (one attack in one yeardespite the treatment).

Gilenya (fingolimod) belongs to the sphingosine-1-phosphate (S1P)receptor modulator class. The indications are the same as those ofnatalizumab, namely the remitting forms with attacks after failure ofinterferons. An international trial is currently ongoing in order toevaluate the efficacy in the primary progressive forms of MS (resultsnot available).

Fampyra is a preparation of fampridine (4-aminopyridine, 1-AP ordalfampridine) in the form of a sustained-released tablet. Thismedicament is indicated for the treatment of the sequalae, in particularof the problems in walking which occur during the remitting forms withsequalae or the progressive forms of the disease. Studies have shownthat Fampyra improves walking in a small proportion of patients.

In the severe forms, the use of immunosuppressants, among whichmitoxantrone, which is more effective than corticoids, but whichcomprises many more side effects, can be proposed. Social andpsychological care is necessary, through integration into patientgroups, keeping a job and, as required, adaptation of the workstation,psychotherapy, treatment for depression or for an anxious state.

It is important to underline that, while the immunosuppressant orimmunomodulatory treatments which are aimed at inhibiting theinflammatory reaction are effective, at the beginning of the disease, indecreasing the number or the duration of the active lesions, they haveonly very little effectiveness on the long-term handicap and have onlylittle or no effectiveness in the progressive (primary or secondary)forms of the disease. As regards the sequalae, only Fampyra looks to bea medicament capable of improving walking in certain patients.

Biotin (or vitamin H) is a ubiquitous water-soluble vitamin which isnaturally found in many foods, such as offal, eggs and certainvegetables. In mammals, biotin acts as a cofactor for four metabolismcarboxylases involved in several key steps of energy metabolism,including pyruvate carboxylase (neoglucogenesis), 3-methylcrotonyl CoAand propionyl CoA carboxylases (catabolism of certain amino acids whichsupply the Krebs cycle with intermediate metabolites), and acetyl CoAcarboxylase (fatty acid synthesis).

Over the past few years, it has also been shown that biotin can regulatethe expression of numerous genes via a mechanism ofbiotinylation/debiotinylation of histones, which are protein structuresthat regulate DNA conformation and, in so doing, the access of certainregions of the genome to transcription factors. It appears that a largenumber of genes of which the expression is regulated by biotin encodeproteins involved in energy metabolism (Zempleni et al., 2009).

Patent application WO 2011124571 describes the use of biotin at a highdose (of the order of 100 to 600 mg/day) for the treatment of visualimpairments, in particular related to optic atrophy. It should be notedthat the visual impairments actually described in this application aresymptoms related to a particular leukoencephalopathy, i.e. aninvolvement of the white matter of the brain. This document neitherdescribes nor suggests that biotin could be used for the treatment ofmultiple sclerosis. Indeed, even though certain symptoms may be similar(visual problems), the etiology is quite different.

Although biotin is indicated in children with a deficiency inbiotinidase or in holocarboxylase synthase, pathology conditions whichare sometimes associated with leukoencephalopathy or with opticneuropathy, the doses necessary are of the order of 10 mg/day duringthese diseases (review in Wolf, 2010).

In the context of the present invention, it has been shown that biotin,in particular at a high dose, can make it possible to improve thecondition of patients suffering from multiple sclerosis.

As it will be seen in the examples, although this improvement has beenobserved in two patients with progressive retrobulbar optic neuritis,biotin can be used in patients exhibiting other syndromes, the etiologyof the disease remaining the same (demyelinization). This is confirmedby the results obtained in a patient with homonymous lateral hemianopsiacaused by damage to the cerebral optic radiations.

The invention thus relates to biotin for use thereof in the treatment ofmultiple sclerosis.

Also subjects of the invention are compositions containing biotin forthe use thereof in the treatment of multiple sclerosis, and also the useof biotin for the production of a medicament intended for the treatmentof multiple sclerosis. The teachings of the invention thus make itpossible to implement treatment methods comprising the administration ofbiotin to patients suffering from multiple sclerosis.

In particular, the biotin can be used for the treatment of theprogressive forms of multiple sclerosis (primary or secondaryprogressive forms).

Likewise, the biotin is used, in the treatment of multiple sclerosis, inorder to allow treatment of the sequalae observed in therelaxing/remitting form, after the attacks.

It can be used alone or in combination with another compound used fortreating multiple sclerosis, in particular a compound as describedabove. The invention therefore covers a composition containing biotinand also another medicament against multiple sclerosis, forsimultaneous, separate or sequential (spread out over time) use in thetreatment of multiple sclerosis.

The biotin is preferentially administered at a high dose, i.e. at a dosegreater than 50 mg per day. Even if a maximum dose is not reallyenvisaged, the latter should not generally exceed 500 mg or 700 mg perday. In that way, a dose at least equal to 1 mg/kg/day, preferably 3mg/kg/day, preferably 5 mg/kg/day, or at least equal to 7.5 mg/kg/day,or even around 10 mg/kg/day, is administered to the patient. Between 50and 700 mg of biotin per day are thus administered to the patients,generally between 50 and 500 mg per day, more preferably between 100 and300 mg per day, generally around 300 mg per day.

In one particular embodiment which is preferred (in particular forproblems of ease of use by the patient), the biotin is in a formsuitable for oral administration. This therefore involves a compositionfor oral administration, which will contain at least 20 mg, preferablyat least 40 mg of biotin, or even 50 mg, 75 mg, 100 mg, 150 mg or 250 mgof biotin. This composition is preferentially for pharmaceutical use andis therefore a medicament. It is understood that each unit dose of thiscomposition contains at least 20 mg, preferably at least 40 mg, or even50 mg, 100 mg, 150 mg or 250 mg of biotin, as active ingredient.

In one particular embodiment, this composition for oral administrationcontains biotin as sole active ingredient, and also excipients, withoutany other active ingredient.

An excipient should be understood to mean any compound forming part ofthe formulation which is intended to act as a simple support, i.e. whichis not intended to have a biological activity.

This composition can be in any form known in the art. In particular, itis in the form of gel capsules, tablets (optionally film-coated), pillsor lozenges. In another embodiment, it is in the form of a syrup. Saidsyrup contains an amount such that it contains at least 20 mg,preferably at least 40 mg, or even 50 mg, 75 mg or 100 mg of biotin perunit dose. The concentration of biotin in this syrup depends on the unitdose that it is desired to give to the patient.

Excipients which can be used by those skilled in the art are well knownin the art. Talc (E553b), microcrystalline cellulose, lactose, starch(in particular corn starch), magnesium stearate (E572) and stearic acid(E570) can thus be chosen. This list is not exhaustive.

When this composition is prepared in the form of 25 gel capsules, apreferred excipient is microcrystalline cellulose.

When the composition is in the form of a film-coated tablet, saidfilm-coating may be formed from any substance known in the art, such ashypromellose (E464), ethylcellulose, macrogol, talc (E553b) titaniumdioxide (E171) or iron oxide (E172).

The active ingredient may also be coloured (by any acceptable colouring,such as cochineal), thereby making it possible to verify that the biotinis well dispersed in the excipient.

In another aspect, the biotin may be in the form which allowsadministration by injection: this then involves an injectablecomposition containing at least 20 mg, preferably at least 40 mg, oreven 50 mg, 75 mg, 100 mg, 150 mg or 250 mg of biotin per unit dose.

This injectable composition may be in the form of a vial containing thebiotin, and also acceptable excipients. The concentration of biotin isadjusted according to the envisaged volume of the vial. Certainexcipients which improve biotin solubility can be used.

The excipients that can be used for the production of injectablecompositions are well known in the art. Mention may in particular bemade of sodium dihydrogen phosphate, sodium bicarbonate (E550i), methylpara-hydroxybenzoate (E218) and propyl para-hydroxybenzoate (E216),which can be used together in proportions that those skilled in the artare capable of determining. The water used is water for injection. Theinjection is preferably carried out intramuscularly. It can also becarried out intravenously.

DESCRIPTION OF THE FIGURES

FIG. 1: Change in the visual, fields (automated campimetry) of patient 3before and after treatment with biotin (100 mg/day) begun on Apr. 12,2012. A to D: right eye; E to H: left eye. A, E: November 2010; B, F:December 2010; C, G: January 2012; D, H: 30 Jun. 2012. The absence ofspontaneous modification of the visual field between November 2010 andJanuary 2012 on three successive examinations should be noted (AC andE-G). The improvement in the visual field in the upper left quadrant inJune 2012, two months after introduction of the biotin treatment, shouldbe noted (D and H). The improvement is marked by lightening of thecomputer plot (arrows).

EXAMPLES

Three patients with a progressive form of multiple sclerosis receivedbiotin.

Description of Clinical Cases Patient 1

This 72-year-old patient had progressive multiple sclerosis with opticinvolvement: right predominant rapid visual acuity decreaseapproximately three years before the treatment.

Three months after the beginning of these problems, the patient received3 infusions of corticoids which led to a significant but transientimprovement in her visual acuity. Two further series of infusions werecarried out 5 and 7 months after the beginning of the sight problems,without any notable effect.

Nine months after the beginning of the problems, the visual acuitycontinued to decrease, going to 1/10 an the right and 5/10 on the left.Eleven months after the beginning of the problems, she could only countfingers on the right and the visual acuity went to 2/10 on the left.

The patient also had paroxysmal problems with walking, described asbalance problems associated with lower limb weakness which each timelasted less than 24 hours.

Two years after the beginning of the problems, treatment with biotin wasbegun at the dose of 100 mg three times a day.

Three months later, the patient noted an improvement in her visualacuity: she could read telephone numbers, she could make out faces andcould read newspaper headlines. The visual acuity was noted at 2/10 onthe left and 5/10 on the right. Balance was more assured, in particularwhen turning round. She could cook alone, which was not the casepreviously. The MRI was unchanged, as was the brain MRI spectra. On theother hand, the visual evoked potentials showed the reappearance of aP100 wave on the left (no response was noted on the fight) of prolongedlatency (126.5 ms).

The treatment was continued at the same dose. After six months oftreatment, the evoked potentials showed the beginnings of a P100 wave onthe right and also an improvement in the latency of the left P100 wave(which went from 126.5 to 111.8 ms, FIG. 3C). The brain MRI spectrashowed a clear decrease in the choline peak and in the choline/creatineratio. The treatment with biotin was increased to 600 mg/day. After ninemonths of treatment, a bilateral P100 wave was noted.

The treatment was then continued at the dose of 300 mg/day for 15months, then 100 mg/day for 9 months.

Between the beginning of the treatment and the date of the last visit,the visual acuity remained stable (2/10 on the left and 5/10 on theright) without any further episode of optic neuropathy. The balance alsoremained stable.

Patient 2

A man born in 1987, without any particular personal history. His familyhistory showed that his mother had multiple sclerosis. The patient had afirst neurological episode in May 2006, characterized by nystagmus, limbpain and a problem with balance, having regressed in 8 days. A secondepisode occurred in February 2008, characterized by fatigue, an episodicsensation of double vision and problems with balance, related to astatic cerebellar syndrome. The search for an autoimmune disease wasnegative. The medullary MRI showed an area of hypersignal at thecervical level. The brain MRI showed numerous areas of hypersignals inthe periventricular white matter, without taking contrast, theappearance of which is compatible with the diagnosis of multiplesclerosis. Treatment with interferon Ib (betaferon) began in February2008. The patient experienced a further diplopia-type attack in July2008 which was regressive after Solumedrol infusions.

Between 2009 and 2012, without the patient having a further attack ofhis disease, he indicated a very insidious and progressive decrease inhis visual acuity. Although the visual acuity was considered to benormal in 2008, in July 2010 the visual acuity of the right eye wasnoted at 2/10 and that of the left eye at 6/10. The evoked potentials(July 2010) show a bilateral slowing of the P100 waves to 140milliseconds, attesting to bilateral involvement of the optic nerves.Three Solumedrol infusions were carried out in September 2010 and then 4infusions between 8 and 11 Aug. 2011, without any effect. The visualacuity in December 2011 went to 1/10 on the right and 3/10 on the left.The papillae are bilaterally pale. OCT (Optical Coherence Tomography)shows a considerable fall in the thickness of the peripapillary nervefibres to 65 microns on the right and 61 microns on the left, confirmingthe bilateral involvement of the optic nerves. The Goldmann visual fieldshows two central and cecocentral scotomas and also an enlargement ofthe blind spot on the right side with a slight degradation compared withthe previous visual field. On the left side, the existence of a centralscotoma, which is also slightly enlarged compared with the previousvisual field, is noted.

The successive MRIs between 2008 and 2011 do not show any increase inthe damage load, indicating that the patient has a progressive form ofmultiple sclerosis characterized by involvement of the optic nerves.

Treatment with biotin was then introduced on 6 Mar. 2012 at the dose of100 mg/day until 30/03 and then 200 mg/day from 6/04 to Jun. 5, 2012then 300 mg/day from Jun. 5, 2012 to Jul. 6, 2012. Two completeopthalmological examinations were carried out during this period oftime: a first on 30/03/2012, which showed no improvement in the visualacuity compared with the examination on 6/03 (before treatment), and asecond on Jul. 6, 2012 (after 3 months of treatment), which showed avery significant improvement in the visual acuity of the left eye, whichwent from 3/10 to 7.5/10.

Patent No. 3

A 29-year-old woman with no personal or family history. In mid-October2004, she presented a left homonymous lateral hemianposia in relation toan inflammatory lesion of the white matter located on the path of theright optic radiations. The examinations had then revealed intrathecalsynthesis of immunoglobulins in the CSF and the evolvement had initiallybeen favourable after 3 infusions of Solumedrol. The symptomologysubsequently reappeared. After 3 infusions of Solumedrol and orthoptictherapy, the evolvement was marked by a functional improvement. InFebruary 2005, the appearance of further visual problems and of afurther right parieto-occipital lesion taking contrast was noted. Theevolvement was gradually favourable. However, a left inferiorquadrantanopia persisted. The visual acuity was at 6/10^(th) on theright and 7/10^(th) on the left. Between 2005 and the end of 2011,fluctuations in the visual acuity were noted, with regressive periods,of worsening on corticoids in November 2005, March 2006 and October2006, with persistence of a left homonymous lateral heminanopsia betweenattacks. From the end of 2008, the visual acuity has been stable at 6/10bilaterally. This stability of the homonymous lateral hemianopsia isdemonstrated by several examinations of she visual field carried outbetween the end of 2010 and the beginning of 2012. In the face of thelack of recovery of the visual acuity, it was decided to begin atreatment with biotin at the dose of 100 mg/day. The visual evokedpotentials carried out at this time were normal, demonstrating that thevisual impairment is not related to an involvement of the optic nervesthemselves, but indeed no a homonymous lateral hemianopsia in relationto the lesions of the white matter of the brain affecting the opticradiations. The treatment with biotin was begun on Dec. 4, 2012 at thedose of 100 mg/day. The new examination of the visual field on30/06/2012 (after 1 and a half months of treatment) shows a clearimprovement in the homonymous lateral hemianopsia (FIG. 1).

Discussion

It was therefore observed that the clinical condition of patient 1 witha secondary progressive form of multiple sclerosis, improved andstabilized under treatment with biotin.

This observation was confirmed in two other patients suffering frommultiple sclerosis with progressive optic neuropathy (patient No. 2) orwith sequalae consisting of involvement of the optic radiations in thewhite matter of the brain (patient No. 3).

To date, these three treated patients have shown an improvementauthenticated on several parameters: magnetic resonance spectroscopy,visual evoked potentials and visual acuity for the first patient, visualacuity and visual field for the second patient, visual field(campimetry) for the third.

In the three cases, the improvement occurred within three monthsfollowing introduction of the treatment, while the analysis of theretrospective data showed stability and/or progressive worsening of thevisual impairment during the 2 years preceding the introduction of thetreatment. In addition to the improvement, stabilization of the symptomsfor the eyes for which there was less improvement was also observed.

Moreover, the motor problems of patient 1 were also corrected and werestabilized.

This represents an important advance since no treatment is currentlyrecognized in the progressive (primary or secondary) forms of multiplesclerosis and also on the symptoms related to sequalae of the disease.

REFERENCES

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1. A method of treating multiple sclerosis, comprising administeringbiotin to a patient in need thereof, wherein said multiple sclerosis isa progressive form of multiple sclerosis.
 2. (canceled)
 3. A method fortreating sequalae after multiple sclerosis attacks in a patient,comprising administering biotin to said patient.
 4. The method of claim1, wherein the daily amount of biotin administered to said patient iscomprised between 50 and 500 mg.
 5. The method of claim 1, wherein theamount of biotin administered to said patient is comprised between 100and 300 mg.
 6. The method of claim 1, wherein said biotin is in a formsuitable for oral administration.
 7. The method of claim 1, wherein saidbiotin is in the form of gel capsules, tablets (optionally film-coated),lozenges or pills.
 8. The method of claim 1, wherein said biotin is inthe form of a composition containing biotin and excipients, without anyother active ingredient.
 9. The method of claim 8, wherein saidexcipients are chosen from talc and microcrystalline cellulose.
 10. Themethod of claim 1, wherein said biotin is in the form of an injectablecomposition.
 11. The method of claim 3, wherein the daily amount ofbiotin administered to said patient is comprised between 50 and 500 mg.12. The method of claim 3, wherein the amount of biotin administered tosaid patient is comprised between 100 and 300 mg.
 13. The method ofclaim 3, wherein said biotin is in a form suitable for oraladministration.
 14. The method of claim 3, wherein said biotin is in theform of gel capsules, tablets (optionally film-coated), lozenges orpills.
 15. The method of claim 3, wherein said biotin is in the form ofa composition containing biotin and excipients, without any other activeingredient.
 16. The method of claim 15, wherein said excipients arechosen from talc and microcrystalline cellulose.
 17. The method of claim3, wherein said biotin is in the form of an injectable composition.